Center for Evolution and Cancer, Helen Diller Family Comprehensive Cancer Center and Department of Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.

Cancer evolution: No simple answers

Traditionally, the evolution of cancer has been explained in simple terms: A cell acquires mutations and becomes malignant and then gives rise to progeny that become more malignant as they acquire additional mutations. A key assumption of this model is that the entire cancer is derived from descendants of a single original cell. However, a new study by Paguirigan et al. challenges this paradigm by providing evidence of convergent evolution in acute myeloid leukemia. The authors analyzed individual cells from multiple patients with leukemia and demonstrated that the mutation patterns seen in each patient could not have arisen from a single ancestral cell, suggesting a need for more sophisticated models of cancer evolution to inform the development of new treatment strategies.

Abstract

Clonal evolution in cancer—the selection for and emergence of increasingly malignant clones during progression and therapy, resulting in cancer metastasis and relapse—has been highlighted as an important phenomenon in the biology of leukemia and other cancers. Tracking mutant alleles to determine clonality from diagnosis to relapse or from primary site to metastases in a sensitive and quantitative manner is most often performed using next-generation sequencing. Such methods determine clonal frequencies by extrapolation of allele frequencies in sequencing data of DNA from the metagenome of bulk tumor samples using a set of assumptions. The computational framework that is usually used assumes specific patterns in the order of acquisition of unique mutational events and heterozygosity of mutations in single cells. However, these assumptions are not accurate for all mutant loci in acute myeloid leukemia (AML) samples. To assess whether current models of clonal diversity within individual AML samples are appropriate for common mutations, we developed protocols to directly genotype AML single cells. Single-cell analysis demonstrates that mutations of FLT3 and NPM1 occur in both homozygous and heterozygous states, distributed among at least nine distinct clonal populations in all samples analyzed. There appears to be convergent evolution and differential evolutionary trajectories for cells containing mutations at different loci. This work suggests an underlying tumor heterogeneity beyond what is currently understood in AML, which may be important in the development of therapeutic approaches to eliminate leukemic cell burden and control clonal evolution-induced relapse.

The targeted genotyping of single acute myeloid leukemia cells is technically feasible, identifies the zygosities of concurrent mutations, and suggests that sequencing of bulk populations may underestimate clonal complexity.

The targeted genotyping of single acute myeloid leukemia cells is technically feasible, identifies the zygosities of concurrent mutations, and suggests that sequencing of bulk populations may underestimate clonal complexity.